A ‘spirit molecule’ from the Amazon could be a game changer in the treatment of major depressive disorders. Dr Carol Routledge, of Small Pharma, talks to Karen Southern about her pioneering work with DMT.

Psychedelic assisted drug therapy is not as ‘far out’ as it sounds – the therapeutic benefits of psychedelics such as LSD have already gained mainstream recognition.

But exciting research into DMT, the ‘spirit molecule’ found in Amazonian brew ayahuasca, is showing real potential to transform mental health care.

DMT is the active compound in ayahuasca, which can spark a short powerful psychoactive experience lasting less than half an hour. This makes it far more accessible for clinical use than other psychedelic compounds whose effects typically last for hours. Combined with professional therapy, the treatment has the potential to shift a patient’s mindset.

In a world-first, Small Pharma has collaborated with Imperial College London to assess how DMT works hand-in-hand with psychotherapy. The Phase I clinical trial is now complete, with very promising results.

Dr Routledge, Chief Medical and Scientific Officer of UK-based Small Pharma, explained: “One of the reasons we selected DMT (N,N-Dimethyltryptamine) is that it induces a short psychedelic experience but has an expected long-duration antidepressant effect.

“The whole treatment, including wraparound therapy and pharmaceutical dosing for DMT (our patented product is called SPL026), is predicted to be about two hours, whereas for other psychedelic candidates – such as psilocybin – it can take a whole day or more.

“This means DMT is more clinically practical to work with. Patients only need to be in the clinic for a relatively short amount of time and this makes it easier to incorporate into health systems around the world.”

Dr Routledge added: “While DMT has unique properties that could help treat major depressive disorders, it is worth highlighting the importance of the therapy that goes with it.

“The DMT acts as a catalyst – offering a powerful hyperconnected experience – but it is the talking therapy, the psychedelic experience in a meaningful way. 

Together, DMT and talking therapy could enable the increase in new neuronal connections in the brain – triggering a rapid-acting antidepressant effect that provides immediate relief from negative, ruminative thought patterns.” In other words, shifting the patient’s mindset helps reset neural connections away from constant negative repetitive loops and back towards normal thought patterns.

Treatment during the clinical trial has been administered in a highly controlled therapeutic setting with an emphasis on safety and trust. The trial started in January 2021, combining a Phase I and Phase IIa study to roll data over immediately. Phase I’s main aim was to understand the the safety, tolerability, mechanistic and pharmacodynamic effects of DMT with therapy – including the intensity and quality of the psychedelic experience – so that a suitable dose could be selected from Phase I and taken into Phase IIa.

Dr Routledge continued: “That dose of SPL026 – our DMT-based product – obviously needs to be safe and well-tolerated, but it also needs to elicit a full breakthrough psychedelic experience in all subjects being treated with an active drug.

“We successfully completed the Phase I component of our study, and we’ve now started the Phase IIa efficacy study, which is a proof-of-concept study in patients with major depressive disorder to assess efficacy and safety of DMT with therapy. We are due to get a headline data set in the first half of this year.”

The psychedelic experience is subjective, so differs from person to person. However, Dr Routledge says visual hallucinations are likely, which could include seeing geometric shapes. There may also be auditory hallucinations, a loss of sense of time and an out-of-body experience. She points out: “You don’t lose a sense of ‘you’, but you can perceive yourself in a slightly different way. Sometimes people will have discussions with themselves. This can be therapeutically beneficial, because people can talk through a lot of their issues.”

The psychotherapy – which is conducted on either side of the DMT dose – first of all ‘sets’ the patient for dosing. Dosing anchors the experience and enables the trial participants to explain their experiences in a safe setting. This is thought to help cement new connections and to inform any next steps with the participant.

Crucially, DMT is not expected to produce significant side-effects. Dr Routledge explained: “There were no serious adverse effects in the Phase I component of our trial. DMT is not anticipated to be addictive or to have abuse liability based on current preclinical and clinical data.”

A successful scale-up will, of course, depend on having therapists with the right skills set; Small Pharma’s training programme launched in July 2021 to provide psychedelic training and training on the bespoke DMT therapy protocol.

Therapists involved in the first session are now working on the Phase IIa clinical trial, with training expanded to cover Phase IIb and Phase III clinical trials.

While Small Pharma is carrying out the world’s first formal trial on DMT and psychotherapy, other companies are focused on other psychedelic candidates. Compass Pathways, another UK company, is developing a patented form of psilocybin (COMP360) for use in conjunction with therapy to treat patients with treatment-resistant depression, and recently reported positive results from their Phase IIb clinical trial.

Dr Routledge continued: “What is exciting is that the UK is quickly forging a leadership position in the world of psychedelic assisted therapy research. This is thanks to the world-leading academic institutions – such as Imperial College London – that are supporting various clinical trials. The government should be delighted that such trailblazing innovation is happening right on its shores and grab the opportunity to lead on the global stage with both hands.”

Regulators’ reactions have so far been positive, she added. “The UK Medicines and Healthcare products Regulatory Agency (MHRA) is supportive of our ambitions. In fact, earlier this year, the MHRA granted Small Pharma an Innovation Passport Designation for SPL026, the lead product from our pipeline of DMT-assisted therapies. Similar to the FDA’s fast-track in the United States, the UK’s MHRA Innovation Passport provides us with access to specialist advice from MHRA partners such as NICE and the NHS throughout the drug development process. This has the potential to enable a speedier, more efficient development process for SPL026 with the aim of accelerating time to market.”

Subject to regulatory approval SPL026 is predicted to reach the market in 2026/27, and across the pond in the US, attitudes towards psychedelics are also changing. Oregon became the first US state to create a legal system for supervised psilocybin experiences; California, Vermont and Hawaii are actively considering new legal frameworks for psychedelics. Meanwhile, John Hopkins Medicine received its first federal grant for psychedelic treatment research in 50 years.

The days of ‘conventional’ anti-depressants – and months and years spent on prescription medications –may well be numbered for millions of people around the world.